Current Organic Chemistry, 2010, 14, 1781-1791 1781

Plant Natural Products in Anticancer Drug Discovery

Paul G. Grothaus*, Gordon M. Cragg and David J. Newman

Natural Products Branch, Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, NCI-Frederick,
Fairview Center, Suite 206, P. O. Box B, Frederick, MD 21702-1201, USA

Abstract: Plant-derived natural products have been an important source of several clinically useful anti-cancer agents. Plants continue to
play a major role in drug discovery as evidenced by the number of promising new agents in clinical development based on selective ac-
tivity against cancer-related molecular targets. Due to improvements in tumor targeting technology, some agents which failed in earlier
clinical studies are also stimulating renewed interest. We wish to draw the attention of readers to the rapidly evolving recognition that a
significant number of natural product drugs/leads are possibly produced by endophytic fungi and microbes residing in the plant tissues.
We consider that this area of natural product research should be expanded significantly.

Keywords: Plant-derived natural products, anticancer, antitumor, targeted agents, endophytes.

1. INTRODUCTION
Throughout most of history, humans have depended upon Na-
ture, especially plants, for medicines with which to treat a wide
spectrum of diseases. Most of the great civilizations have developed
sophisticated traditional medicine systems. Egyptian medicine dates
back to 2900 BCE, but the best known record is the "Ebers Papy-
rus" which dates from 1500 BCE and documents over 700 drugs,
mostly of plant origin. Records documenting the uses of approxi-
mately 1000 plant-derived substances in Mesopotamia date from
around 2600 BCE, and many are still used today for the treatment
of ailments ranging from coughs and colds to parasitic infections
and inflammation [1]. Extensive documentation of the Chinese
Materia Medica has occurred over the centuries [2], with the first
record dating from about 1100 BCE (Wu Shi Er Bing Fang, con-
taining 52 prescriptions), being followed by works such as the
Shennong Herbal (~100 BCE; 365 drugs) and the Tang Herbal (659
CE; 850 drugs). Likewise, documentation of the Indian Ayurvedic
system dates from before 1000 BCE (Charaka; Sushruta and Samhi-
tas with 341 and 516 drugs respectively) [3, 4]. In the ancient
Western World, the Greeks and Romans made substantial contribu-
tions to the rational development of the use of herbal drugs, with
Dioscorides, a Greek physician (100 CE), accurately recording the
collection, storage, and use of medicinal herbs during his travels
with Roman armies throughout the then "known world", and Galen
(130-200 CE.), a practitioner and teacher of pharmacy and medicine
in Rome, being well known for his complex prescriptions and for-
mulae used in compounding drugs. The preservation of much of the
Greco-Roman expertise during the Dark and Middle Ages (5th to
12th centuries) may be attributed to the Arabs who expanded it to
include the use of their own resources, together with Chinese and
Indian herbs unknown to the Greco-Roman world. Details of these
contributions to the history of medicine are presented at the website
of the National Library of Medicine (NLM), U.S. National Insti-
tutes of Health (NIH), at www.nlm.nih.gov/hmd/medieval/ara-
bic.html.
Advances in scientific knowledge eventually led to the discov-
ery that pure bioactive compounds, commonly referred to as natural
*Address correspondence to this author at the Natural Products Branch, Developmental
Therapeutics Program, Division of Cancer Treatment and Diagnosis, NCI-Frederick,
Fairview Center, Suite 206, P. O. Box B, Frederick, MD 21702-1201, USA;
Tel: 301-846-5387; Fax: 301-846-6178; E-mail: grothausp@mail.nih.gov
products (NPs), could be isolated from plants. The first reported
example was the isolation of morphine from opium in 1804 [5].
This ushered in a new era in medicine where drugs could be puri-
fied from plants and administered in precise dosages independent of
the source or age of the plant material.
The quest for agents that may ameliorate the scourge of the
manifold diseases clustered under the term “cancer” started in ear-
nest in the 1950s with the discovery and development of the vinca
alkaloids and the isolation of the cytotoxic podophyllotoxins. As a
result, the United States National Cancer Institute (NCI) initiated an
extensive plant collection program in 1960, focused mainly in tem-
perate regions. This led to the discovery of many novel chemotypes
showing a range of cytotoxic activities [6], including the taxanes
and camptothecins. This plant collection program was terminated in
1982, but the development of new screening technologies led to the
revival of collections of plants and other organisms in 1986, with a
focus on the tropical and sub-tropical regions of the world.
Chemical and pharmaceutical research expanded greatly during
the 20th century. Living organisms proved to be a rich source of
bioactive compounds. While some of these could be used directly
as drugs, advances in synthetic chemistry also allowed NPs to serve
as leads for the development of semi-synthetic and synthetic ana-
logs with improved pharmacological properties [7]. Today, NPs and
derivatives have proven to be useful probes to elucidate the role of
specific cellular pathways in both normal and tumor cells [8].
Even with the explosive growth of synthetic medicinal chemis-
try during the 1980s and 1990s, NPs continue to be a valuable
source of new drugs. Newman et al. classified drugs as N (an un-
modified natural product); ND (a modified natural product); S (a
synthetic compound with no natural product conception); S/NM (a
synthetic compound showing competitive inhibition of the natural
product substrate); S* (a synthetic compound with a natural product
pharmacophore); and S*/NM; (a synthetic compound with a natural
product pharmacophore showing competitive inhibition of the natu-
ral product substrate) [9, 10]. As of June 2009, the 164 small mole-
cule compounds available to the physician (depending upon their
individual country) as antitumor agents can be categorized as fol-
lows: N (25; 17%), ND (50; 31%), S (42; 26%), S/NM (16; 10%),
S* (20; 12%) and S*/NM (7; 4%).
Recently, Bailly published a similar analysis, using a somewhat
different series of definitions where only “direct and slightly modi-
fied natural products are counted as such”, demonstrating the influ-

1385-2728/10 $55.00+.00 © 2010 Bentham Science Publishers Ltd.

1782 Current Organic Chemistry, 2010, Vol. 14, No. 16 Grothaus et al.

ence of natural product scaffolds. Readers should consult his article
for further information [11].
This review is to update previous reviews on the subject [12-19]
and, therefore, has concentrated on agents in development and late
discovery.
2. PLANT-DERIVED ANTI-CANCER AGENTS IN CLINI-
CAL USE
Plant-derived NPs play a prominent role in the clinical treat-
ment of cancer. These agents can be categorized into four major
compound classes: the bisindole (vinca) alkaloids, the epipodophyl-
lotoxins, the taxanes, and the camptothecins. These classes will
only be briefly discussed here as they have been covered quite well
in a multiplicity of reviews and books over the last few years, with
current examples being the articles by Hostettmann and Marston
[15], Potterat and Hamburger [19], and Cragg and Newman [20].
Vinca Alkaloids
The first agents to advance into clinical use were the vinca alka-
loids, vinblastine (1) and vincristine (2), isolated from the Mada-
gascar periwinkle, Catharanthus roseus G. Don. (Apocynaceae).
The vinca alkaloids disrupt microtubules, causing the arrest of the
cells at metaphase and leading to apoptotic cell death. More recent
semi-synthetic analogs of these agents are vinorelbine (3) and
vindesine (4). These agents are primarily used in combination with
other cancer chemotherapeutic drugs for the treatment of a variety
of cancers, including leukemias, lymphomas, advanced testicular
cancer, breast and lung cancers, and Kaposi’s sarcoma. Some ef-
forts continue to improve the safety and efficacy of this class. A
bifluorinated derivative of vinorelbine, vinflunine (5), is currently
in Phase III clinical trials [13, 21, 22].
Epi-Podophyllotoxins
Podophyllotoxin (6) was first isolated in 1880 from Podophyl-
lum peltatum Linnaeus (commonly known as the American man-
drake or Mayapple) (Podophyllaceae), and Podophyllum emodii
Wallich from the Indian subcontinent. Like the vinca alkaloids,
podophyllotoxin disrupts formation of the mitotic spindle. Podo-
phyllotoxin and several closely related lignans were introduced into
clinical trials, only to be dropped due to lack of efficacy and unac-
ceptable toxicity. Extensive research led to the development of
etoposide (VM 26) (7) and teniposide (VP 16-213) (8), semisyn-
thetic glucosidic acetals of epi-podophyllotoxin, as clinically effec-
tive agents which are used in the treatment of lymphomas and bron-
chial and testicular cancers. In contrast to podophyllotoxin,
etoposide and teniposide have little effect on tubulin polymerization
but inhibit topoisomerase II activity. They stabilize the DNA-
enzyme cleavable complex leading to double-stranded DNA breaks
[23].
Taxanes
One of the most important classes of chemotherapeutic drugs is
the taxanes. The parent compound, paclitaxel (Taxol®) (9), initially
was isolated from the bark of the Pacific Yew, Taxus brevifolia
Nutt. (Taxaceae), in 1971. The taxanes act by stabilizing microtu-
bulin formation, causing cell cycle arrest in M phase and cell death.
This unique mode of action sparked intense interest in the taxanes
but their development was impeded by supply and formulation
issues. Paclitaxel and its semisynthetic analog docetaxel (10) finally

OH
N N

N N N N
H H
H3CO2C H3CO2C
H H
H3CO H3CO
OCOCH3 OCOCH3
N N
H CO2CH3 H CO2CH3
HO HO
R CH3
1; R = CH3 2; R = CHO 3
vincristine vinblastine vinorelbine

OH F
N N F

N N N N
H H
H3CO2C H3CO2C
H H
H3CO H3CO
OH OCOCH3
N N
H CO2NH2 H CO2CH3
HO HO
CH3 CH3
4 5
vindesine vinflunine
Plant Natural Products in Anticancer Drug Discovery Current Organic Chemistry, 2010, Vol. 14, No. 16 1783

R and NSCLC. Paclitaxel has also attracted attention in the potential

O treatment of multiple sclerosis, psoriasis and rheumatoid arthritis.
O
In addition, 23 taxanes are in preclinical development as potential
HO O anti-cancer agents [24-26].
OH
O
OH Camptothecins
O
O
Another important addition to the anti-cancer drug armamen-
O tarium is the class of clinically active agents derived from camp-
O
tothecin (11), which is isolated from the Chinese ornamental tree,
O Camptotheca acuminata Decne (Nyssaceae) (Rahier et al., 2005).
O
Camptothecin (as its sodium salt) was advanced to clinical trials by
the NCI in the 1970s, but was dropped because of severe bladder
H3CO OCH3
H3CO OCH3 toxicity, but extensive research led to the development of more
OH
OH effective derivatives, topotecan (Hycamtin®) (12) and irinotecan
S
6 (CPT-11; Camptosar®) (13). Topotecan is used for the treatment of
podophyllotoxin 7; R = CH3 8; R = ovarian and small cell lung cancers, while irinotecan is used for the
etoposide teniposide treatment of colorectal cancers [27, 28].

entered clinical use in the early 1990s. Paclitaxel is used in the Other Plant-derived Clinical Agents
treatment of breast, ovarian, and non-small cell lung cancer
(NSCLC), and has also shown efficacy against Kaposi sarcoma, Besides these four major compound classes, two additional
while docetaxel is primarily used in the treatment of breast cancer plant-derived agents in clinical use are homoharringtonine (HHT)

O O

O O OH O O OH

O O O O

N O H O O N O H O
H H
OH OH O OH OH O

O O O O
O O

9 10
paclitaxel (Taxol®) docetaxel (Taxotere®)

O HO O
N N
N N
O O

11 OH O 12 OH O
camptothecin topotecan (Hycamtin®)

N O O
N
O
N
O
13
irinotecan (Camptosar®) OH O
1784 Current Organic Chemistry, 2010, Vol. 14, No. 16
(14), isolated from the Chinese tree, Cephalotaxus harringtonia var.
drupacea (Sieb and Zucc.) (Cephalotaxaceae) [29], and elliptinium
(Celiptium®) (15), a derivative of ellipticine, isolated from species
of several genera of the Apocynaceae family, including Bleekeria
vitensis A.C. Sm., a Fijian medicinal plant with reputed anti-cancer
properties [30, 31]. A racemic mixture of harringtonine and homo-
harringtonine has been used successfully in China for the treatment
of acute myelogenous leukemia (AML) and chronic myelogenous
leukemia (CML). Purified homoharringtonine has shown efficacy
against various leukemias, including some resistant to standard
treatment, and has been reported to produce complete hematologic
remission (CHR) in patients with late chronic phase CML. This
compound is undergoing a new set of Phase II clinical trials under
the auspices of ChemGenex (Australia/USA). Elliptinium is mar-
keted in France for the treatment of breast cancer.
O
N O
O OCH3
H
O
HO OCH3
O
OH
O
H3CO
14
homoharringtonine (HHT)
CH2
N entered into Phase I and then Phase II clinical trials against a broad
HO Ac O inhibitor of CDK-7 and -9, the kinases primarily responsible for
N gets/interactions involved in the transcription processes and fla-
H
15
elliptinium (Celiptium®)
3. PLANT-DERIVED ANTI-CANCER AGENTS IN CLINI-
CAL DEVELOPMENT
Combretastatins
The combretastatins were isolated from the South African
“bush willow”, Combretum caffrum (Eckl. & Zeyh.) Kuntze (Com-
bretaceae), collected in southern Africa in the 1970s as part of a
random collection program for the NCI by the USDA, working in
collaboration with the Botanical Research Institute of South Africa
[32, 33]. Species of the Combretum and Terminalia genera, both of
which belong to the Combretaceae family, are used in African and
Indian traditional medicine for the treatment of a variety of dis-
eases, including hepatitis and malaria, and several Terminalia spe-
cies have reportedly been used in the treatment of “cancer”.
The combretastatins are a family of stilbenes which act as vas-
cular disrupting agents selectively targeting the endothelial cells
lining the tumor vasculature. They cause disruption of the tubulin
cytoskeleton and remodeling of the actin cytoskeleton, inducing a
dramatic change in the three dimensional shape of immature endo-
thelial cells. The cells change shape from flat to round, stopping
blood flow through the capillary, starving the tumor of nutrients and
causing tumor cell death. This mechanism of action differentiates
Grothaus et al.
the combretastatins from angiogenesis inhibitors that are designed
to work by preventing the growth of new blood vessels.
A water-soluble analog, combretastatin A4 phosphate (CA4)
(16), has shown promise in early clinical trials, and a number of
combretastatin analogs are being developed. Three are in clinical
trials, while 11 are in preclinical development. This chemical class
has served as a model for the synthesis of a host of analogs contain-
ing the essential trimethoxy aryl moiety linked to substituted aro-
matic moieties through a variety of two or three atom bridges in-
cluding heterocyclic rings and sulfonamides, and provides an im-
pressive display of the power of a relatively simple natural product
structure to spawn a prolific output of medicinal and combinatorial
chemistry [32].
H3CO
H3CO
O Na
O P
O Na
OCH3
16
combretistatin A4 phosphate (CA4)
Flavopiridol
The flavone, flavopiridol (Alvocidib®) (17) is totally synthetic,
but its novel structure is based on the natural product rohitukine
(18) isolated from Dysoxylum binectariferum. Flavopiridol was
originally considered to be an inhibitor of cyclin dependent kinases
(the regulators of the G2 to M transition in the cell cycle), and was
range of tumors [34]. It has now been reported to be a very potent
promoting RNA polymerase II (RNAP II) activity, thus involving
these agents in the transcription process. The molecular tar-
vopiridol interactions have been reviewed [35, 36]. Currently, the
compound is reported to be in nine clinical trials ranging from
Phase I to Phase II covering leukemias, lymphomas and solid tu-
mors either as single agent or in combination with other anticancer
agents in the NCI’s clinical trial website and is reported in the
Prous Integrity® database to be in Phase III trials under the auspices
of Sanofi-Aventis.
OH O OH O
Cl
HO HO O
OH OH
N
N
CH3 CH3
17 18
flavopriidol (Alvocidib®) rohitukine
Roscovitine
Olomucine (19), originally isolated from the cotyledons of the
radish, Raphanus sativus L. (Brassicaceae) [37] was shown to in-
hibit cyclin-dependent kinases (Cdk), proteins which play a major
role in cell cycle progression. This finding disproved the existing
Plant Natural Products in Anticancer Drug Discovery Current Organic Chemistry, 2010, Vol. 14, No. 16 1785

dogma that no specific kinase inhibitors could be found for ATP-

binding sites since they would be swamped by the presence of ex-
cess of ATP. O
H
NH

N
N
OH
N O HO
HN N OH
CH3
O
23
OH ingenol 3-angelate (PEP005)
19 O
olomucine
Further development of this series using combinatorial chemis- O O
try techniques led to roscovitine (Selicicib®) (20), purvalanol A
(21) and purvalanol B (22). Olomucine and roscovitine are very O H
potent inhibitors of CDK-7 and -9. The purvalanols demonstrated
improved potency, with IC50 values in the 4 to 40 nM range, com- O
pared to 450 nM for roscovitine [38]. The R-isomer of roscovitine OR
is currently in phase II under the auspices of Cyclacel with reports 24; R = H 25; R = C(O)CH2CH2CO2H
of clinical trials in Europe. Although some beneficial effects are triptolide TriptoSar®
observed with signal transduction inhibitors (STIs) alone, complete
or partial responses tend only to be demonstrated when sequential Targeted Agents
treatments of STI/cytotoxin are used, so also with R-roscovitine,
A recurring liability of natural products, at least in the area of
sequential treatment with cytotoxins is being used and/or considered.
cancer chemotherapy, is that while often very potent, they have
R
limited solubility in aqueous solvents and exhibit narrow therapeu-
NH tic indices. These factors have resulted in the demise of a number of
pure natural products. Interesting however, a number of older
N
N agents have now entered preclinical and clinical trials as “war-
Cl NH
heads” linked to various delivery systems.
HN N N
N Maytansine (26) was isolated in the early 1970s from the Ethio-
N
pian plant, Maytenus serrata (Hochst. Ex A. Rich.) Wilczek (Celas-
HN N N traceae), again collected for the NCI through the USDA random
OH collection program [6]. Unfortunately, very promising activity in
20 OH
preclinical animal testing did not translate into significant efficacy
roscovitine (Selicicib®) 21; R = H 22; R = CO2H in clinical trials, and it was dropped from further study in the early
purvalanol A purvalanol B 1980s. Two derivatives of maytansine, DM1 and DM4, in fact de-
rivatized bacterial metabolites that are (probably) on the path to
Ingenol-3-Angelate maytansine as this agent is now known to be predominately bacte-
rial in origin [42], are in clinical trials. The formal structures of
The common Australian plant Euphorbia peplus (Euphorbiaceae) DM1 and DM4 with various conjugates are given in the recent arti-
is widely used as a home remedy for various skin conditions. Clini- cle by Ikeda et al. [43], which should be read in conjunction with
cal studies with crude E. peplus sap in the 1970s provided compel- the commentary by Polson and Sliwkowski [44] in order to put the
ling evidence of efficacy [39]. The active agent was identified as a results in perspective.
hydrophobic diterpene ester, ingenol-3-angelate (PEP005) (23). The
O
antitumor activity of ingenol-3-angelate is mediated through activa-
O
tion of protein kinase C (PKC) [39, 40]. A topical formulation of the N
compound, developed by the Australian company Peplin, is currently O
H3C
in Phase II trials for the treatment of actinic keratoses and basal cell Cl O H CH3
carcinoma. Phase I trials, with alternative formulations, for the treat- N O
H3CO
ment of acute myeloid leukemia and bladder cancer are planned.
H
Triptolide O

Triptolide (24) is a diterpenoid isolated from the Chinese per-

N O
ennial vine Triptergium wilfordi. While triptolide shows potent OH
anticancer activity, the mechanism of action is not well understood H
O
26 CH3
and toxicity problems have hampered its clinical development [41].
maytansine
TriptoSar (PG490-88Na) (25), a succinyl derivative of triptolide, is
in Phase I clinical trials for the treatment of solid tumors by Phar- Currently, huN901-DM1 (BB-10901), which targets the CD56
magenesis, in collaboration with Pierre Fabre [13]. epitope, is in three Phase I and II trials under the auspices of Immu-
1786 Current Organic Chemistry, 2010, Vol. 14, No. 16 Grothaus et al.

nogen. The same warhead, but now linked to the Roche antibody O
O
trastuzumab, is in one Phase III trial against breast cancer and in 10
other Phase I and II trials in a variety of tumour types under the O
O H O
name TDM-1, with a significant number of other antibody combi-
nations in preclinical studies. With a slight variation in the warhead O
structure giving the compound known as DM4, there are two con-
OH
structs (BT-062 and HuC242-DM4) in Phase I clinical trials at the
O OH
current time, with Biotest and Sanofi-Aventis respectively. Re- O
cently, two other DM4 constructs, AVE-9633 and hu242-DM4
were discontinued, the former for toxicity reasons in Phase I and O
27
the latter for business reasons by Immunogen. thapsigargin

A recent discussion of the techniques involved and some of the

results with other such antibody-warhead constructs has recently
been published by Senter of Seattle Genetics and should be con-
sulted by interested readers [45]. This should be read in concert
with the discussion by Stephan et al. [46] of the problems involved
in assaying such conjugates from a pharmacokinetics aspect in or-
der to appreciate the problems involved in assessing the value of
such conjugates.
Another case of considerable interest is that of thapsigargin
(27), isolated from the umbelliferous plant, Thapsia garganica L.
(Apiaceae), collected on the Mediterranean island of Ibiza [47].
Thapsigargin induces apoptosis (cell death) in quiescent and prolif-
erating prostate cancer cells, and while it does not show selectivity
for prostate cancer cells, it has been conjugated to a small peptide
carrier to produce a water-soluble prodrug which is specifically
activated by prostate specific antigen (PSA) protease at metastatic
prostate cancer sites. Treatment of animals bearing prostate cancer
xenograft tumors demonstrated complete tumor growth inhibition
without significant toxicity. Given that the prodrug is stable in hu-
man plasma, it holds promise as a treatment for human prostate
cancer.
Folate linked conjugates are being used to specifically deliver
“warheads” to tumors. The vinblastine skeleton has been used as a
warhead, in the form of a desacetylvinblastine hydrazide folate
conjugate 28 [48]. Under the code name EC-145, it is in Phase II
clinical trials against platinum resistant ovarian cancer under the
sponsorship of Endocyte.
4. PLANT-DERIVED ANTI-CANCER AGENTS IN PRE-
CLINICAL DEVELOPMENT
A number of plant-derived NPs are under preclinical develop-
ment. The following discussion is not exhaustive but focuses on
those NPs of highest interest.
Bruceantin
An “old” drug of the same vintage as paclitaxel and camptothe-
cin having a possibility of revival is bruceantin (29) which was first
isolated from a tree, Brucea antidysenterica J.F. Mill. (Simarouba-
ceae), used in Ethiopia for the treatment of “cancer” [49]. As often
happens, activity was observed in animal models bearing a range of
tumors, but no objective responses were observed in clinical trials,
and further development was terminated. Recent observations of
significant activity against panels of leukemia, lymphoma and mye-
loma cell lines, as well as in animal models bearing early and ad-
vanced stages of the same cancers, has revived interest. This activ-
ity has been associated with the down-regulation of a key oncopro-
tein (c-MYC), and these data are being presented as strong evidence
supporting the development of bruceantin as an agent for the treat-
ment of hematological malignancies.
Indirubins
The indirubins have been identified as the major active compo-
nents of the traditional Chinese medicine formulation known as
Danggui Longhui Wan, which has been used for many years to treat
CML in China [50]. Of importance from both a natural product and

H
N NH2
O
O OH NH
O O O OH O
H H H
N N N
O N N N OH
H H H
N O O O
OH OH S
HN N
H
S
O O
H2N N N
HO O
N O
OH
N HN NH
H

OH O
28 N H
EC-145
NH
O
O O
Plant Natural Products in Anticancer Drug Discovery Current Organic Chemistry, 2010, Vol. 14, No. 16 1787

a pharmacological perspective, the indirubins were recognized as ties including impairment of the ribosome recruitment step of trans-
being inhibitors of several CDKs and potent inhibitors of glycogen lation initiation by affecting the composition of the eukaryotic ini-
synthase kinase-3 (GSK-3) [51]. Included in this study were 6- tiation factor (eIF) 4F complex.
bromoindirubin (30), first isolated from Nature from the mollusk HO O
Hexaplex trunculus [37], and its chemically modified oxime deriva- CH3O
HO
tive BIO (31), and these two compounds demonstrated an at least 5- OCH3
fold specificity versus CDK1/cyclin B and/or CDK/p25, and sig-
nificantly greater specificity against a wide range of other kinases.
Significantly, GSK-3 is also an important target in both Alzheimer's O O
disease and type 2 diabetes, and although indole derivatives have
not been reported as being associated with pharmacological inter- HO O
O
vention in these specific disease areas, their potential must be con- R1 R2
sidered quite high. The treatment potential for inhibitors of GSK-3, OCH3
including a listing of other natural product-related structures serv- 32; R1 = H, R2 = OH 33; R1 = OH, R2 = H
ing as possible inhibitors in these disease states, has recently been Silvestrol epi-Silvestrol
reviewed [52], Using the same basic suite of compounds, it was
The compound is in the NCI’s preclinical pipeline and work is
demonstrated that indirubins serve as ligands for the 'orphan recep-
progressing on studies related to pharmacology and pharmacokinet-
tor' known as the aryl hydrocarbon receptor (AhR) [53]. No other
ics expanding upon work at UIC and OSU, with the aim of develop-
natural ligands have yet been identified for AhR, even though, con-
ing the agent as a potential drug lead.
trary to earlier beliefs, it has existed for over 450 million years.
Indole-containing compounds, however, had been suggested as
natural ligands for AhR slightly earlier [54]. Full details of the Withacnistin
chemistry involved, and SARs established using X-ray crystallog- The very interesting STAT 3 inhibitor withacnistin A (34) was
raphy and molecular modeling techniques, have been published first reported by Sebti’s group under the name cucurbitacin Q [59].
[55]. Later work in conjunction with NCI chemists showed that the
OH O molecule was in fact withacnistin A, a compound first reported by
HO the Kupchan group in the late 1960s [60, 61]. This molecule, a ster-
O O oidal type triterpene, was shown by the Sebti group to be a potent
O O inhibitor of Stat 3 both in vitro and in vivo even though it was in an
impure form, with later work with the purified and correctly identi-
O fied molecule demonstrating that the activity seen was due to
HO O O withacnistin. This compound is currently under early preclinical
H
development under collaboration between the Sebti group at the
29
bruceantin
University of South Florida and the NCI.

Br HO
O N
NH
NH
N N
H H
O O
30 31
6-bromoindirubin 6-bromoindirubin oxime (BIO)
Rocaglates
The cyclopenta[b]benzofuran compounds known generically as
rocaglates are known to be toxic to insects and tumour cells, are
protein synthesis inhibitors and induce arrest at the G2/M stage of
the cell cycle [56]. With continuing work on these interesting mole-
cules, the Kinghorn group, initially at the University of Illinois at
Chicago (UIC) and now at the Ohio State University (OSU) have
shown that the most active of the molecules is silvestrol (32) and its
slightly less active epimer, epi-silvestrol (33). From work by the
clinical group at OSU, 32 has been shown to have a selective activ-
ity against B cells in patient-derived chronic lymphocytic leukae-
mia (CLL) cells relative to normal peripheral blood monocytes.
Subsequent studies both ex vivo and in vivo using the Tcl-1 trans-
genic murine model confirmed the T-cell sparing activity [57]. Sub-
sequently, a number of studies from two groups, the UIC/OSU
researchers and their associates [17] and Pelletier’s group at McGill
[58], have shown that the molecule has a series of interesting activi-
Br O
H
O
O
O
O
H
H H
O 34
HO withacnistin A
Betulinic Acid
Betulinic acid (35), another plant-derived compound with a
long history, is a lupane-type triterpene which has been isolated
from many taxonomically diverse plant genera [62]. A major source
is the birch tree, Betula spp. (Betulaceae), which is also a primary
source of its C28 alcohol precursor, betulin, whose isolation was
first reported in 1788. A variety of biological activities have been
reported for 35, including anti-bacterial, anti-inflammatory and
antimalarial, but the most important activities have been associated
with inhibition of the replication of strains of the human immu-
nodeficiency virus (HIV), and cytotoxicity against a range of cancer
cell lines. Significant in vivo activity has been observed in animal
models bearing human melanoma xenografts, and the NCI is assist-
ing in the development of systemic and topical formulations of the
agent for potential clinical trials.
1788 Current Organic Chemistry, 2010, Vol. 14, No. 16 Grothaus et al.

collected in the Dominican Republic. Using the NCI in vivo hollow

fiber model, (-)-alvaradoin E demonstrated significant growth inhi-
bition at the injection site when tested with KB, LNCaP, and Col2
H
cells [68]. Further experiments demonstrated that the cytotoxicity of
OH (-)-alvaradoin E was mediated by apoptosis. (-)-Alvaradoin E de-
creased cell viability 8.6-fold and increased DNA cleavage 10-fold
O within 36 hours of exposure [68].
H
O O
HO
H OH O
35
betulinic acid

2-Cyano-3,12-dioxoolean-1,9-dien-28-oic Acid (CDDO)

O O
Triterpenoid acids, such as oleanolic and ursolic acid which are
37 38
common plant constituents, are associated with weak anti-
b-lapachol b-lapachone
inflammatory and anti-tumor activities. Programs to synthesize new
analogs having increased potencies have led to the synthesis of 2- OH O OH
cyano-3,12-dioxoolean-1,9-dien-28-oic acid (36) (CDDO) and its
methyl ester, which exhibit potent in vitro and in vivo anti-tumor
activity against a wide range of tumors, including breast carcino-
mas, leukemias, and pancreatic carcinomas [63]. CDDO shows H
significant activity against epithelial ovarian carcinoma (EOC) cell H O
lines, including lines which were resistant to clinically used agents HO O
such as cisplatin. Since EOC is the leading cause of death from O
gynecologic cancers, further evaluation of CDDO in the treatment
HO OH
of these cancers is being pursued [64]. 39
alvaradoin E

O
H Sodium Pancratistatin 3,4-O-Cyclic Phosphate
OH In 1986, Pettit and colleagues reported the isolation of gram
N
C quantities of the potent cytotoxin (+)-pancratistatin (40), a phenan-
O thridone alkaloid, from the bulbs of the plant Pancratium littorale
Jacq (Amaryllidaceae) [69]. This plant has now been re-identified
O as Hymenocallis littoralis Salisb. Subsequently, pancratistatin was
H 36 synthesized [70, 71] and shown mechanistically to target mitochon-
CDDO dria in human lymphoma cells, resulting in apoptosis by activation
of caspase-3 and flipping phosphatidyl serine to the outer leaflet of

-Lapachone the plasma membrane [72]. Pancratistatin also caused caspase-3
The relatively simple naphthoquinone
-lapachol (37) is a well- activation in the Jurkat (human T-cell leukemia) cell line, and acti-
known compound obtained from the bark of the lapacho tree, Tabe- vated the Fas receptor within membranous lipid rafts [73]. Despite
buia avellanedae, and other species of the same genus which are considerable interest in (+)-pancratistatin as a potential anticancer
native to South America.
-Lapachol and other plant components and antiviral agent, preclinical drug formulation was hindered by
are extensively used as ethnobotanical treatments in the Amazonian the poor water solubility and bioavailability of this compound. Re-
region, and
-lapachol was advanced to clinical status by the Na- cently, Pettit and colleagues reported the synthesis of (+)-
tional Cancer Institute (NCI) in the 1970s. It was later withdrawn pancratistatin 3,4-O-cyclic phosphate sodium salt (41) [74] which
due to unacceptable levels of toxicity, but its close relative
- Shnyder and colleagues demonstrated is also potently cytotoxic for
lapachone (38) has demonstrated interesting molecular target activ- cancer cell lines [75]. Moreover, the salt was demonstrated to have
ity, with one mechanism of action being the induction of apoptosis efficacy in a DLD-1 human colon tumor model, causing necrosis
in transformed cells [65]. Evidence of its involvement in transcrip- and decrease in functional vasculature at the MTD of 100 mg/kg
tion processes has been reported demonstrating that the agent in- [75]. (+)-Pancratistatin is not a new natural product, however, this
duced activation of caspase-3, inhibition of NFB and subsequent approach to rendering this alkaloid more water soluble appears to
downregulation of bcl-2 [66]. Currently,
-lapachone (ARQ501) is be highly effective and may revive interest in the compound.
in phase II clinical trials in the US for advanced solid tumors, and HO HO O
OH O
further information on the background of these agents may be ob- P
tained from a 2004 review [67]. O O O O
OH

Alvaradoin E NH NH Na
O O
(-)-Alvaradoin E (39) is the most active of ten anthracenone C- OH O OH O 41
glycosides isolated by bioactivity-directed fractionation of an ex- 40 sodium pancratistatin
tract of the leaves of Alvaradoa haitiensis Urb (Picramniaceae), pancratistatin 3,4-O-cyclic phosphate
Plant Natural Products in Anticancer Drug Discovery
5. PLANT METABOLITES AND THE FUNGAL CONNEC-
TION
Until a few years ago, the question as to whether plants were
the actual source of some of the very important antitumor-active
materials isolated from them by chemists, would probably have led
to a series of somewhat derisory comments from most scientists but
from work over the last few years, this question is now reminiscent
of similar comments / questions made by marine natural products
chemists 20 or so years ago with respect to sponge-derived mole-
cules.
Over the last 15 or so years, and particularly in the last 5 or so
years, with easier access to work performed in the People’s Repub-
lic of China, a significant number of reports have shown that the
four major classes of “plant-derived” molecules, the taxanes, camp-
tothecins, podophyllotoxins and even the vinca alkaloids have now
had numbers of endophytic fungi isolated, purified, fermented on
significant scales, up to 10 litres in some cases, that produce the
same molecules that were originally isolated from the plants them-
selves. Strobel at Montana State had demonstrated over 15 years
ago that a new genus of endophytic fungus isolated from Taxus
trees (that “produced / contained” paclitaxel) would produce very
small amounts of the compound when fermented in the laboratory.
This finding was later extended to identify the sources as Taxomy-
ces [76] and many Pestalotiopsis species [77]. Following on from
these reports came realization that this was not an isolated phe-
nomenon, as over the years camptothecin [78, 79], podophyllotoxin
[80, 81], vinblastine [82], and vincristine [83, 84] have been re-
ported to be produced by fermentation of endophytic fungi isolated
from the original source plants.
That very specific control mechanisms are in play in these fungi
can be demonstrated by the work of Keller’s group on the common
soil fungus, Aspergillus nidulans and its control of expression of the
40 plus “cryptic secondary metabolite clusters” that her group has
identified from sequence studies [85] where they demonstrated the
presence of a control protein LaeA. Over the last two years or so, a
number of related investigations have been reported from soil fungi
with five recent papers, one primary, demonstrating discovery of
the emericellamide (42) biosynthetic pathway [86], and four review
papers covering aspects of activation of fungal secondary metabo-
lite genes [87-90]. The identification of the gene / gene product
controlling metabolite production by these microbes could provide
an entry into greatly increased production of key bioactive natural
products, and produce a large number of previously unknown active
materials, not necessarily only antitumor agents, that will require
the skills of synthetic and medicinal chemists in the near future.
H H
N N
O [2]
O O O Ed. CRC Press: Boca Raton, FL, 1999; p. 512.
NH O [3]
O H
N [4]
N Environ. Health Perspect., 1999, 107, 783-9.
H [5]
O morphine for postoperative pain relief. Can. J. Anaesth. J., 2000, 47, 367-74.
42
Emericellamide A
In addition, these discoveries also bring up the intriguing possi-
bility that there exists some form of signalling analogous to “bacte-
rial quorum sensing” involving these fungal endophytes, the plant
itself and production of toxic secondary metabolites when attacked
by a predator. Such a system would make more “economic sense”
Current Organic Chemistry, 2010, Vol. 14, No. 16 1789
from the perspective of “energy balances” rather than postulating
production centrally, followed by transport to the region under at-
tack and then removal of a material that is toxic to the host as well
as the predator. However this suggestion is simply an intriguing
hypothesis from arguing by analogy.
6. CONCLUSIONS
Plants have been a prime source of highly effective conven-
tional drugs for the treatment of many forms of cancer, and while
the actual compounds isolated from the plant frequently may not
serve as the drugs, they provide leads for the development of poten-
tial novel agents. As new technologies are developed, some of the
agents which failed earlier clinical studies are now stimulating re-
newed interest. The ability to attach agents to carrier molecules
directed to specific tumors, shows promise for effectively targeting
highly cytotoxic NPs to the tumors while avoiding their toxic side
effects on normal healthy tissues. With the rapid identification of
new proteins having significant regulatory effects on tumor cell
cycle progression, and their conversion into targets for high
throughput screening, molecules isolated from plants and other
natural organisms are proving to be an important source of novel
inhibitors of the action of these key proteins, and have the potential
for development into selective anti-cancer agents.
Finally, it is interesting to speculate as to the “producers” of the
plant secondary metabolites that are in use as either antitumor drugs
or as leads to newer structures. Recent work on the biosynthetic
machinery of the vinca alkaloids in hairy root cultures of C. roseus
does not appear to invoke endophytic microbes, but the cultures,
though outwardly sterile, have not been checked for the presence of
endophytes (Personal Communication, Sarah O’Connor, MIT).
Only time will tell as to whether some of the metabolites now iso-
lated from plants have a “microbe in their background”, though
recently Horinouchi published a paper on the combinatorial biosyn-
thesis of plant medicinal polyketides in microorganisms which
makes very interesting reading [91]. This paper should also be read
in conjunction with his earlier work with Streptomyces reporting the
discovery of the type III PKS known as RppA [92] and cou-
marate/cinnamate:CoA ligase [93], which were once considered to
be plant specific enzymes.
NOTE
This review reflects the opinions of the authors, not necessarily
those of the U.S. Government.
REFERENCES
[1] Borchardt, J. K. The Beginnings of Drug Therapy: Ancient Mesopotamian
Medicine. Drug News Perspect., 2002, 15, 187-192.
Huang, K. C.; Williams, W. M. The Pharmacology of Chinese Herbs: 2nd
Kapoor, L. D. Handbook of Ayurvedic Medicinal Plants: Herbal Reference
Library. CRC Press: Boca Raton, FL, 2000; p. 424.
Dev, S. Ancient-modern concordance in Ayurvedic plants: some examples.
Hamilton, G. R.; Baskett, T. F. In the arms of Morpheus the development of
[6] Cassady, J. M.; Douros, J.D. Anticancer Agents Based on Natural Product
Models. Academic Press: New York, 1980.
[7] Newman, D. J.; Cragg, G. M. Natural Product Scaffolds as Leads to Drugs.
Future. Med. Chem., 2009, 1, 1415-1427.
[8] Newman, D. J.; Cragg, G. M.; Holbeck, S.; Sausville, E. A. Natural products
and derivatives as leads to cell cycle pathway targets in cancer chemother-
apy. Curr. Cancer Drug Targets, 2002, 2, 279-308.
[9] Newman, D. J.; Cragg, G. M. Natural products as sources of new drugs over
the last 25 years. J. Nat. Prod., 2007, 70, 461-77.
[10] Newman, D. J.; Cragg, G. M.; Snader, K. M. Natural products as sources of
new drugs over the period 1981-2002. J. Nat. Prod., 2003, 66, 1022-37.
1790 Current Organic Chemistry, 2010, Vol. 14, No. 16
[11] Bailly, C. Ready for a comeback of natural products in oncology. Biochem.
Pharmacol., 2009, 77, 1447-57.
[12] Balunas, M. J.; Kinghorn, A. D. Drug discovery from medicinal plants. Life
Sci., 2005, 78, 431-41.
[13] Butler, M. S. Natural products to drugs: natural product-derived compounds
in clinical trials. Nat. Prod. Rep., 2008, 25, 475-516.
[14] Cragg, G. M.; Newman, D. J. Plants as a source of anti-cancer agents. J.
Ethnopharmacol., 2005, 100, 72-9.
[15] Hostettmann, K.; Marston, A. The search for new drugs from higher plants.
Chimia 2007, 61, 322-326.
[16] Hostettmann, K.; Marston, A. Plants as a still unexploited source of new
drugs. Nat. Prod. Commun., 2008, 3, 1307-1315.
[17] Kinghorn, A. D.; Chin, Y.-W.; Swanson, S. M. Discovery of natural product
anticancer agents from biodiverse organisms. Curr. Opin. Drug. Discov. De-
vel., 2009, 12, 189-96.
[18] Li, J. W.-H.; Vederas, J. C. Drug discovery and natural products: end of an
era or an endless frontier? Science 2009, 325, 161-5.
[19] Potterat, O.; Hamburger, M. Drug discovery and development with plant-
derived compounds. Prog. Drug Res., 2008, 65, 45, 47-118.
[20] Cragg, G. M.; Newman, D. J. Nature: A vital source of leads for anticancer
drug development. Phytochem. Rev., 2009, 8, 313-331.
[21] Gueritte, F.; Fahy, J. The Vinca Alkaloids. In Anticancer Agents from Natu-
ral Products, Cragg, G. M.; Kingston, D. G. I.; Newman, D. J., Eds. CRC
Press LLC: Boca Raton, Fla, 2005; pp 123-135.
[22] Bennouna, J.; Campone, M.; Delord, J. P.; Pinel, M.-C. Vinflunine: a novel
antitubulin agent in solid malignancies. Expert. Opin. Investig. Drugs., 2005,
14, 1259-67.
[23] Lee, K.; Xiao, Z. Antitumor agents 240. Podophyllotoxins and Analogs. In
Anticancer Agents from Natural Products, Cragg, G. M.; Kingston, D. G. I.;
Newman, D. J., Eds. CRC Press LLC: Boca Raton, Fla, 2005; pp 71-87.
[24] Kingston, D. Tubulin-Interactive Natural Products as Anticancer Agents (1).
J. Nat. Prod., 2009.
[25] Kingston, D. G. Taxol and its Analogs. In Anticancer Agents from Natural
Products Cragg, G. M.; Kingston, D. G. I.; Newman, D. J., Eds. CRC Press
LLC: Boca Raton, Fla, 2005; pp 89-122.
[26] Kingston, D. G. I.; Newman, D. J. Taxoids: cancer-fighting compounds from
nature. Curr. Opin. Drug. Discov. Dev., 2007, 10, 130-44.
[27] Cragg, G. M.; Newman, D. J. A Tale of Two Tumor Targets: Topoisomerase
I and Tubulin. The Wall and Wani Contribution to Cancer Chemotherapy. J.
Nat. Prod., 2004, 67, 232-244.
[28] Rahier, N. J.; Thomas, C. J.; Hecht, S. M. Camptothecin and its analogs. In
Anticancer Agents from Natural Products, Cragg, G. M.; Kingston, D. G. I.;
Newman, D. J., Eds. CRC Press LLC: Boca Raton, Fla, 2005; pp 5-21.
[29] Itokawa, H.; Wang, X.; Lee, K.-H. Homoharringtonine and related com-
pounds. In Anticancer Agents from Natural Products, Cragg, G. M.; King-
ston, D. G. I.; Newman, D. J., Eds. CRC Press LLC: Boca Raton, Fla, 2005;
pp 47-70.
[30] Auclair, C. Multimodal action of antitumor agents on DNA: the ellipticine
series. Arch. Biochem. Biophys., 1987, 259, 1-14.
[31] Hamburger, M.; Marston, A.; Hostettmann, K. Search for new drugs of plant
origin. In Advances in drug research, Testa, B., Ed. Academic Press: 1991;
Vol. 20, pp 167-215.
[32] Li, Q.; Sham, H. L. Discovery and development of antimitotic agents that
inhibit tubulin polymerisation for the treatment of cancer. Expert. Opin.
Ther. Pat., 2002, 12, 1663-1702.
[33] Pinney, K. G.; Jelinek, C.; Edvardsen, K.; Chaplin, D. J.; Pettit, G. R. The
discovery and development of the combretastatins. In Anticancer Agents
from Natural Products, Cragg, G. M.; Kingston, D. G. I.; Newman, D. J.,
Eds. CRC Press LLC: Boca Raton, Fla, 2005; pp 23-46.
[34] Christian, M. C.; Pluda, J. M.; Ho, P. T. C.; Arbuck, S. G.; Murgo, A. J.;
Sausville, E. A. Promising new agents under development by the Division of
Cancer Treatment, Diagnosis, and Centers of the National Cancer Institute.
Semin. Oncol., 1997, 24, 219-240.
[35] Fischer, P. M.; Gianella-Borradori, A. Recent progress in the discovery and
development of cyclin-dependent kinase inhibitors. Expert. Opin. Investig.
Drugs., 2005, 14, 457-77.
[36] Mayer, F.; Mueller, S.; Malenke, E.; Kuczyk, M.; Hartmann, J. T.; Boke-
meyer, C. Induction of apoptosis by flavopiridol unrelated to cell cycle arrest
in germ cell tumour derived cell lines. Investig. New. Drugs., 2005, 23, 205-
11.
[37] Meijer, L.; Raymond, E. Roscovitine and other purines as kinase inhibitors.
From starfish oocytes to clinical trials. Acc. Chem. Res., 2003, 36, 417-25.
[38] Chang, Y. T.; Gray, N. S.; Rosania, G. R.; Sutherlin, D. P.; Kwon, S.; Nor-
man, T. C.; Sarohia, R.; Leost, M.; Meijer, L.; Schultz, P. G. Synthesis and
application of functionally diverse 2,6,9-trisubstituted purine libraries as
CDK inhibitors. Chem. Biol., 1999, 6, 361-75.
[39] Hampson, P.; Chahal, H.; Khanim, F.; Hayden, R.; Mulder, A.; Assi, L. K.;
Bunce, C. M.; Lord, J. M. PEP005, a selective small-molecule activator of
protein kinase C, has potent antileukemic activity mediated via the delta iso-
form of PKC. Blood 2005, 106, 1362-8.
[40] Hampson, P.; Kavanagh, D.; Smith, E.; Wang, K.; Lord, J. M.; Ed Rainger,
G. The anti-tumor agent, ingenol-3-angelate (PEP005), promotes the re-
cruitment of cytotoxic neutrophils by activation of vascular endothelial cells
in a PKC-delta dependent manner. Cancer. Immunol. Immunother., 2008, 57,
1241-51.
Grothaus et al.
[41] Wang, X.; Matta, R.; Shen, G.; Nelin, L. D.; Pei, D.; Liu, Y. Mechanism of
triptolide-induced apoptosis: Effect on caspase activation and Bid cleavage
and essentiality of the hydroxyl group of triptolide. J. Mol. Med., 2006, 84,
405-15.
[42] Yu, T.; Floss, H. G., Ansamitocins (maytansinoids). In Anticancer Agents
from Natural Products, Cragg, G. M.; Kingston, D. G. I.; Newman, D. J.,
Eds. CRC Press LLC: Boca Raton, Fla, 2005; pp 321-337.
[43] Ikeda, H.; Hideshima, T.; Fulciniti, M.; Lutz, R. J.; Yasui, H.; Okawa, Y.;
Kiziltepe, T.; Vallet, S.; Pozzi, S.; Santo, L.; Perrone, G.; Tai, Y.-T.; Cirstea,
D.; Raje, N. S.; Uherek, C.; Dälken, B.; Aigner, S.; Osterroth, F.; Munshi,
N.; Richardson, P.; Anderson, K. C. The monoclonal antibody nBT062 con-
jugated to cytotoxic Maytansinoids has selective cytotoxicity against CD138-
positive multiple myeloma cells in vitro and in vivo. Clin. Cancer. Res.,
2009, 15, 4028-37.
[44] Polson, A. G.; Sliwkowski, M. X. Toward an effective targeted chemotherapy
for multiple myeloma. Clin. Cancer. Res., 2009, 15, 3906-7.
[45] Senter, P. D. Potent antibody drug conjugates for cancer therapy. Curr. Opin.
Chem. Biol., 2009, 13, 235-44.
[46] Stephan, J.-P.; Chan, P.; Lee, C.; Nelson, C.; Elliott, J. M.; Bechtel, C.; Raab,
H.; Xie, D.; Akutagawa, J.; Baudys, J.; Saad, O.; Prabhu, S.; Wong, W. L.
T.; Vandlen, R.; Jacobson, F.; Ebens, A. Anti-CD22-MCC-DM1 and MC-
MMAF conjugates: impact of assay format on pharmacokinetic parameters
determination. Bioconjug. Chem., 2008, 19, 1673-83.
[47] Denmeade, S. R.; Jakobsen, C. M.; Janssen, S.; Khan, S. R.; Garrett, E. S.;
Lilja, H.; Christensen, S. B.; Isaacs, J. T. Prostate-specific antigen-activated
thapsigargin prodrug as targeted therapy for prostate cancer. J. Natl. Cancer.
Inst., 2003, 95, 990-1000.
[48] Low, P. S.; Kularatne, S. A. Folate-targeted therapeutic and imaging agents
for cancer. Curr. Opin. Chem. Biol., 2009, 13, 256-62.
[49] Cuendet, M.; Pezzuto, J. M. Antitumor activity of bruceantin: an old drug
with new promise. J. Nat. Prod., 2004, 67, 269-72.
[50] Xiao, Z.; Hao, Y.; Liu, B.; Qian, L. Indirubin and meisoindigo in the treat-
ment of chronic myelogenous leukemia in China. Leuk. Lymphoma., 2002,
43, 1763-8.
[51] Meijer, L.; Skaltsounis, A. L.; Magiatis, P.; Polychronopoulos, P.; Knockaert,
M.; Leost, M.; Ryan, X. P.; Vonica, C. A.; Brivanlou, A.; Dajani, R.;
Crovace, C.; Tarricone, C.; Musacchio, A.; Roe, S. M.; Pearl, L.; Greengard,
P. GSK-3-selective inhibitors derived from Tyrian purple indirubins. Chem.
Biol., 2003, 10, 1255-66.
[52] Cohen, P.; Goedert, M. GSK3 inhibitors: development and therapeutic poten-
tial. Nat. Rev. Drug. Discov., 2004, 3, 479-87.
[53] Knockaert, M.; Blondel, M.; Bach, S.; Leost, M.; Elbi, C.; Hager, G. L.;
Nagy, S. R.; Han, D.; Denison, M.; Ffrench, M.; Ryan, X. P.; Magiatis, P.;
Polychronopoulos, P.; Greengard, P.; Skaltsounis, L.; Meijer, L. Independent
actions on cyclin-dependent kinases and aryl hydrocarbon receptor mediate
the antiproliferative effects of indirubins. Oncogene 2004, 23, 4400-12.
[54] Denison, M. S.; Nagy, S. R. Activation of the aryl hydrocarbon receptor by
structurally diverse exogenous and endogenous chemicals. Annu. Rev. Phar-
macol. Toxicol., 2003, 43, 309-34.
[55] Polychronopoulos, P.; Magiatis, P.; Skaltsounis, A. L.; Myrianthopoulos, V.;
Mikros, E.; Tarricone, A.; Musacchio, A.; Roe, S. M.; Pearl, L.; Leost, M.;
Greengard, P.; Meijer, L. Structural basis for the synthesis of indirubins as
potent and selective inhibitors of glycogen synthase kinase-3 and cyclin-
dependent kinases. J. Med. Chem., 2004, 47, 935-46.
[56] Lee, S. K.; Cui, B.; Mehta, R. R.; Kinghorn, A. D.; Pezzuto, J. M. Cytostatic
mechanism and antitumor potential of novel 1H-cyclopenta[b]benzofuran
lignans isolated from Aglaia elliptica. Chem. Biol. Interact., 1998, 115, 215-
28.
[57] Lucas, D. M.; Edwards, R. B.; Lozanski, G.; West, D. A.; Shin, J. D.; Vargo,
M. A.; Davis, M. E.; Rozewski, D. M.; Johnson, A. J.; Su, B.-N.; Goettl, V.
M.; Heerema, N. A.; Lin, T. S.; Lehman, A.; Zhang, X.; Jarjoura, D.; New-
man, D. J.; Byrd, J. C.; Kinghorn, A. D.; Grever, M. R. The novel plant-
derived agent silvestrol has B-cell selective activity in chronic lymphocytic
leukemia and acute lymphoblastic leukemia in vitro and in vivo. Blood, 2009,
113, 4656-66.
[58] Cencic, R.; Carrier, M.; Galicia-Vázquez, G.; Bordeleau, M.-E.; Sukarieh, R.;
Bourdeau, A.; Brem, B.; Teodoro, J. G.; Greger, H.; Tremblay, M. L.; Porco,
J. A.; Pelletier, J. Antitumor activity and mechanism of action of the cy-
clopenta[b]benzofuran, silvestrol. PLoS ONE 2009, 4, e5223.
[59] Sun, J.; Blaskovich, M. A.; Jove, R.; Livingston, S. K.; Coppola, D.; Sebti, S.
M. Cucurbitacin Q: a selective STAT3 activation inhibitor with potent anti-
tumor activity. Oncogene., 2005, 24, 3236-45.
[60] Kupchan, S. M.; Anderson, W. K.; Bollinger, P.; Doskotch, R. W.; Smith, R.
M.; Renauld, J. A. S.; Schnoes, H. K.; Burlingame, A. L.; Smith, D. H. Tu-
mor inhibitors. XXXIX. Active principles of Acnistus arborescens. Isolation
and structural and spectral studies of withaferin a and withacnistin. J. Org.
Chem., 1969, 34, 3858-3866.
[61] Sun, J.; Blaskovich, M. A.; Jove, R.; Livingston, S. K.; Coppola, D.; Sebti, S.
M. Cucurbitacin Q: A selective STAT3 activation inhibitor with potent anti-
tumor activity (Oncogene (2005) 24, (3236-3245) DOI:
10.1038/sj.onc.1208470) ). Oncogene., 2008, 27, 1344.
[62] Cichewitz, R. H.; Kouzi, S. A. Chemistry, biological activity, and che-
motherapeutic potential of betulinic acid for the prevention and treatment of
cancer and HIV infection. Med. Res. Rev., 2004, 24, 90-114.
Plant Natural Products in Anticancer Drug Discovery
[63] Couch, R. D.; Browning, R. G.; Honda, T.; Gribble, G. W.; Wright, D. L.;
Sporn, M. B.; Anderson, A. C. Studies on the reactivity of CDDO, a promis-
ing new chemopreventive and chemotherapeutic agent: implications for a
molecular mechanism of action. Bioorg. Med. Chem. Lett., 2005, 15, 2215-9.
[64] Melichar, B.; Konopleva, M.; Hu, W.; Melicharova, K.; Andreeff, M.;
Freedman, R. S. Growth-inhibitory effect of a novel synthetic triterpenoid, 2-
cyano-3,12-dioxoolean-1,9-dien-28-oic acid, on ovarian carcinoma cell lines
not dependent on peroxisome proliferator-activated receptor-gamma expres-
sion. Gynecol. Oncol., 2004, 93, 149-54.
[65] Li, Y.; Sun, X.; LaMont, J. T.; Pardee, A. B.; Li, C. J. Selective killing of
cancer cells by beta -lapachone: direct checkpoint activation as a strategy
against cancer. Proc. Natl. Acad. Sci. USA, 2003, 100, 2674-8.
[66] Choi, B. T.; Cheong, J.; Choi, Y. H. beta-Lapachone-induced apoptosis is
associated with activation of caspase-3 and inactivation of NF-kappaB in
human colon cancer HCT-116 cells. Anticancer. Drugs., 2003, 14, 845-50.
[67] Ravelo, A. G.; Estévez-Braun, A.; Chávez-Orellana, H.; Pérez-Sacau, E.;
Mesa-Siverio, D. Recent studies on natural products as anticancer agents.
Curr. Top. Med. Chem., 2004, 4, 241-65.
[68] Mi, Q.; Lantvit, D.; Reyes-Lim, E.; Chai, H.; Phifer, S. S.; Wani, M. C.;
Wall, M. E.; Tan, G. T.; Cordell, G. A.; Farnsworth, N. R.; Kinghorn, A. D.;
Pezzuto, J. M. Apoptotic anticancer effect of alvaradoin E isolated from Al-
varadoa haitiensis. Anticancer. Res., 2005, 25, 779-87.
[69] Pettit, G. R.; Gaddamidi, V.; Herald, D. L.; Singh, S. B.; Cragg, G. M.;
Schmidt, J. M.; Boettner, F. E.; Williams, M.; Sagawa, Y. Antineoplastic
agents, 120. Pancratium littorale. J. Nat. Prod., 1986, 49, 995-1002.
[70] Pettit, G.; Melody, N.; Herald, D. Antineoplastic agents. 450. Synthesis of
(+)-pancratistatin from (+)-narciclasine as relay. J. Org. Chem., 2001, 66,
2583-2587.
[71] Kim, S.; Ko, H.; Kim, E.; Kim, D. Stereocontrolled total synthesis of pancra-
tistatin. Org. Lett., 2002, 4, 1343-5.
[72] Kekre, N.; Griffin, C.; McNulty, J.; Pandey, S. Pancratistatin causes early
activation of caspase-3 and the flipping of phosphatidyl serine followed by
rapid apoptosis specifically in human lymphoma cells. Cancer. Chemother.
Pharmacol., 2005, 56, 29-38.
[73] Griffin, C.; McNulty, J.; Hamm, C.; Pandey, S. Pancratistatin a novel highly
selective anti-cancer agent that induces apoptosis by the activation of mem-
brane-Fas-receptor associated caspase-3. In Cell apoptosis research trends,
Zhang, C. V.; Figgins, H. C., Eds. Nova Science Publishers: Hauppauge,
NY, 2007; pp 93-107.
[74] Pettit, G. R.; Melody, N.; Herald, D. L. Antineoplastic agents. 511. Direct
phosphorylation of phenpanstatin and pancratistatin. J. Nat. Prod., 2004, 67,
322-7.
[75] Shnyder, S. D.; Cooper, P. A.; Millington, N. J.; Gill, J. H.; Bibby, M. C.
Sodium pancratistatin 3,4-O-cyclic phosphate, a water-soluble synthetic de-
rivative of pancratistatin, is highly effective in a human colon tumor model.
J. Nat. Prod., 2008, 71, 321-4.
[76] Stierle, A.; Strobel, G.; Stierle, D. Taxol and taxane production by Taxomy-
ces andreanae, an endophytic fungus of Pacific yew. Science., 1993, 260,
214-216.
[77] Li, J. Y.; Sidhu, R. S.; Bollon, A.; Strobel, G. A. Stimulation of taxol produc-
tion in liquid cultures of Pestalotiopsis microspora. Mycol. Res., 1998, 102,
461-464.
Received: 11 December, 2009 Revised: 13 December, 2009
Current Organic Chemistry, 2010, Vol. 14, No. 16 1791
[78] Amna, T.; Puri, S. C.; Verma, V.; Sharma, J. P.; Khajuria, R. K.; Musarrat, J.;
Spiteller, M.; Qazi, G. N. Bioreactor studies on the endophytic fungus Entro-
phospora infrequens for the production of an anticancer alkaloid camptothe-
cin. Can. J. Microbiol., 2006, 52, 189-196.
[79] Puri, S. G.; Verma, V.; Amna, T.; Qazi, G. N.; Spiteller, M. An endophytic
fungus from Nothapodytes foetida that produces camptothecin. J. Nat. Prod.,
2005, 68, 1717-1719.
[80] Eyberger, A. L.; Dondapati, R.; Porter, J. R. Endophyte fungal isolates from
Podophyllum peltatum produce podophyllotoxin. J. Nat. Prod., 2006, 69,
1121-1124.
[81] Puri, S. C.; Nazir, A.; Chawla, R.; Arora, R.; Riyaz-Ul-Hasan, S.; Amna, T.;
Ahmed, B.; Verma, V.; Singh, S.; Sagar, R.; Sharma, A.; Kumar, R.;
Sharma, R. K.; Qazi, G. N. The endophytic fungus Trametes hirsuta as a
novel alternative source of podophyllotoxin and related aryl tetralin lignans.
J. Biotechnol., 2006, 122, 494-510.
[82] Guo, B.; Li, H.; Zhang, L. Isolation of a fungus producing vinblastineIsola-
tion of a fungus producing vinblastine. Yunnan Daxue Xuebao, Ziran Kexue-
ban 1998, 20, 214-215.
[83] Yang, X.; Zhang, L.; Guo, B.; Guo, S. Preliminary study of a vincristine-
producing endophytic fungus isolated from leaves of Catharanthus
roseusPreliminary study of a vincristine-producing endophytic fungus iso-
lated from leaves of Catharanthus roseus. Zhong Cao Yao 2004, 35, 79-81.
[84] Zhang, L.; Guo, B.; Li, H.; Zeng, S.; Shao, H.; Gu, S.; Wei, R., Isolation of
endophytic fungus of Catharanthus roseus and its fermentation to produce
products of therapeuticIsolation of endophytic fungus of Catharanthus roseus
and its fermentation to produce products of therapeutic. Zhong Cao Yao
2000, 31, 805-807.
[85] Bok, J. W.; Hoffmeister, D.; Maggio-Hall, L. A.; Murillo, R.; Glasner, J. D.;
Keller, N. P. Genomic mining for Aspergillus natural products. Chem., Biol.,
2006, 13, 31-7.
[86] Chiang, Y.-M.; Szewczyk, E.; Nayak, T.; Davidson, A. D.; Sanchez, J. F.;
Lo, H.-C.; Ho, W.-Y.; Simityan, H.; Kuo, E.; Praseuth, A.; Watanabe, K.;
Oakley, B. R.; Wang, C. C. C. Molecular genetic mining of the Aspergillus
secondary metabolome: discovery of the emericellamide biosynthetic path-
way. Chem. Biol., 2008, 15, 527-32.
[87] Brakhage, A. A.; Schuemann, J.; Bergmann, S.; Scherlach, K.; Schroeckh,
V.; Hertweck, C. Activation of fungal silent gene clusters: a new avenue to
drug discovery. Progr. Drug Res. Fort. 2008, 66, 1, 3-12.
[88] Fox, E. M.; Howlett, B. J. Secondary metabolism: regulation and role in
fungal biology. Curr. Opin. Microbiol., 2008, 11, 481-7.
[89] Hoffmeister, D.; Keller, N. P. Natural products of filamentous fungi: en-
zymes, genes, and their regulation. Nat. Prod. Rep., 2007, 24, 393-416.
[90] Stadler, M.; Keller, N. P. Paradigm shifts in fungal secondary metabolite
research. Mycol. Res., 2008, 112, 127-30.
[91] Horinouchi, S. Combinatorial biosynthesis of plant medicinal polyketides by
microorganisms. Curr. Opin. Chem. Biol., 2009, 13, 197-204.
[92] Funa, N.; Ohnishi, Y.; Fujii, I.; Shibuya, M.; Ebizuka, Y.; Horinouchi, S. A
new pathway for polyketide synthesis in microorganisms. Nature., 1999,
400, 897-9.
[93] Kaneko, M.; Ohnishi, Y.; Horinouchi, S. Cinnamate:coenzyme A ligase from
the filamentous bacterium streptomyces coelicolor A3(2). J. Bacteriol., 2003,
185, 20-7.
Accepted: 15 December, 2009